Endoscopic ultrasound—guided fine needle aspiration in the diagnosis of mediastinal masses of unknown origin

The ability of endosonography to diagnose a variety of gastrointestinal pathology has been significantly advanced with the introduction of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy. EUS-FNA technology can also be applied to the evaluation of non-GI disorders. The role of EUS-FNA to establish the diagnosis of unexplained mediastinal masses has not been previously described. The aim of this study was to determine the diagnostic accuracy, impact on subsequent workup, and role of EUS-FNA in treating mediastinal masses of unknown cause. METHODS : A total of 26 patients (15 men and 11 women, mean age 61 yr, range 39–77 yr) underwent EUS-FNA in patients presenting with unexplained mediastinal masses at four tertiary referral centers. Presenting symptoms included: chest pain (10 patients), dysphagia (eight), cough (seven), fever (six), night sweats (three), and no symptoms/abnormal x-ray (five patients). Five of 26 patients had prior history of cancer (three lung, one tracheal, and one esophageal). RESULTS : Final diagnosis using EUS-FNA, surgery, autopsy, other diagnostic study, or long-term follow-up was available in all patients. EUS-FNA results were classified under three disease categories: 1) infectious, 2) benign/inflammatory, and 3) malignant. Final diagnosis included infectious in five patents, benign/inflammatory in nine, and malignant in 12. EUS-FNA was successful in 21 of 26 patients (81%) for all disease categories (infectious 60%, benign/inflammatory 78%, and malignant 92%). EUS-FNA was successful in directing subsequent workup in 77% (20 of 26) and therapy in 73% (19 of 26). Mean EUS-FNA passes for adequate tissue sampling was lower of nonmalignant disease categories (3.0 and 3.4) versus malignant disease (4.4). No complications were seen during the course of this study. CONCLUSIONS : EUS-FNA in patients presenting with idiopathic mediastinal masses establishes the diagnosis in the vast majority of cases, particularly for those with malignant disease. The emergence of transesophageal EUS-FNA of the mediastinum provides the ability to alter subsequent workup and therapy, obviating the need for more invasive diagnostic studies such as thoracotomy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72588/1/j.1572-0241.2002.06023.x.pd

Lymph Node Characterization in Vivo Using Endoscopic Ultrasound Spectrum Analysis With Electronic Array Echo Endoscopes

Our purpose was to demonstrate the use of radiofrequency spectral analysis to distinguish between benign and malignant lymph nodes with data obtained using electronic array echo endoscopes, as we have done previously using mechanical echo endoscopes. In a prospective study, images were obtained from eight patients with benign-appearing lymph nodes and 11 with malignant lymph nodes, as verified by fine-needle aspiration. Midband fit, slope, intercept, correlation coefficient, and root-mean-square (RMS) deviation from a linear regression of the calibrated power spectra were determined and compared between the groups. Significant differences were observable for mean midband fit, intercept, and RMS deviation (t test P \u3c 0.05). For benign (n = 16) vs. malignant (n = 12) lymph nodes, midband fit and RMS deviation provided classification with 89 % accuracy and area under receiver operating characteristic (ROC) curve of 0.95 based on linear discriminant analysis. We concluded that the mean spectral parameters of the backscattered signals from electronic array echo endoscopy can provide a noninvasive method to quantitatively discriminate between benign and malignant lymph nodes

Biopsy depth after radiofrequency ablation of dysplastic Barrett's esophagus

After endoscopic radiofrequency ablation (RFA) of dysplastic Barrett's esophagus (BE), endoscopic biopsy samples are obtained to assess response to therapy. Whether these biopsies are of adequate depth to assess efficacy is unknown

Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas

BACKGROUND: Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barrett's esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC). METHODS: We genotyped 144 individuals in 42 multiplex pedigrees chosen from 1000 singly ascertained BE/EAC pedigrees, and performed both model‐based and model‐free linkage analyses, using S.A.G.E. and other software. Segregation models were fitted, from the data on both the 42 pedigrees and the 1000 pedigrees, to determine parameters for performing model‐based linkage analysis. Model‐based and model‐free linkage analyses were conducted in two sets of pedigrees: the 42 pedigrees and a subset of 18 pedigrees with female affected members that are expected to be more genetically homogeneous. Genome‐wide associations were also tested in these families. RESULTS: Linkage analyses on the 42 pedigrees identified several regions consistently suggestive of linkage by different linkage analysis methods on chromosomes 2q31, 12q23, and 4p14. A linkage on 15q26 is the only consistent linkage region identified in the 18 female‐affected pedigrees, in which the linkage signal is higher than in the 42 pedigrees. Other tentative linkage signals are also reported. CONCLUSION: Our linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC

Recurring Translocations in Barrett’s Esophageal Adenocarcinoma

Barrett’s esophagus (BE) is a premalignant metaplasia in patients with chronic gastroesophageal reflux disease (GERD). BE can progress to esophageal adenocarcinoma (EA) with less than 15% 5-year survival. Chromosomal aneuploidy, deletions, and duplication are early events in BE progression to EA, but reliable diagnostic assays to detect chromosomal markers in premalignant stages of EA arising from BE are lacking. Previously, we investigated chromosomal changes in an in vitro model of acid and bile exposure-induced Barrett’s epithelial carcinogenesis (BEC). In addition to detecting changes already known to occur in BE and EA, we also reported a novel recurring chromosomal translocation t(10:16) in the BE cells at an earlier time point before they undergo malignant transformation. In this study, we refine the chromosomal event with the help of fluorescence microscopy techniques as a three-way translocation between chromosomes 2, 10, and 16, t(2:10;16) (p22;q22;q22). We also designed an exclusive fluorescent in situ hybridization for esophageal adenocarcinoma (FISH-EA) assay that detects these chromosomal breakpoints and fusions. We validate the feasibility of the FISH-EA assay to objectively detect these chromosome events in primary tissues by confirming the presence of one of the fusions in paraffin-embedded formalin-fixed human EA tumors. Clinical validation in a larger cohort of BE progressors and non-progressors will confirm the specificity and sensitivity of the FISH-EA assay in identifying malignant potential in the early stages of EA

RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas

Esophageal adenocarcinoma (EAC) is a deadly cancer with increasing incidence in the U.S., but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene-fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pre-treatment EAC and 49 non-malignant biopsy tissues from patients undergoing endoscopy for Barrett’s esophagus. In this cohort, we identified 21 novel candidate EAC-associated fusions occurring in 3.33%-11.67% of EACs. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pre-treatment EAC (N=115) and non-malignant (N=183) biopsy tissues. In particular, we observed RPS6KB1–VMP1 gene fusion as a recurrent event occurring in ~10% of EAC cases. Notably, EAC cases harboring RPS6KB1–VMP1 fusions exhibited significantly poorer overall survival as compared to fusion-negative cases. Mechanistic investigations established that the RPS6KB1–VMP1 transcript coded for a fusion protein which significantly enhanced the growth rate of non-dysplastic Barrett’s esophagus cells. Compared to the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1–VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1–VMP1 as a genetic fusion that promotes EAC by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas

Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett’s esophagus

We report a biomarker-based non-endoscopic method for detecting Barrett’s esophagus (BE), based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma (EAC). Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve (AUC)=0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals, who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 minutes. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE

Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm

Barrett’s esophagus (BE) is often asymptomatic and only a small portion of BE patients are currently diagnosed and under surveillance. Therefore, it is important to develop risk prediction models to identify high-risk individuals with BE. Familial aggregation of BE and esophageal adenocarcinoma (EAC), and the increased risk of EAC for individuals with a family history, raise the necessity of including genetic factors in the prediction model. Methods to determine risk prediction models using both risk covariates and ascertained family data are not well-developed

EUS-derived criteria for distinguishing benign from malignant metastatic solid hepatic masses

Background Detection of hepatic metastases during EUS is an important component of tumor staging. Objective To describe our experience with EUS-guided FNA (EUS-FNA) of solid hepatic masses and derive and validate criteria to help distinguish between benign and malignant hepatic masses. Design Retrospective study, survey. Setting Single, tertiary-care referral center. Patients Medical records were reviewed for all patients undergoing EUS-FNA of solid hepatic masses over a 12-year period. Interventions EUS-FNA of solid hepatic masses. Main Outcome Measurements Masses were deemed benign or malignant according to predetermined criteria. EUS images from 200 patients were used to create derivation and validation cohorts of 100 cases each, matched by cytopathologic diagnosis. Ten expert endosonographers blindly rated 15 initial endosonographic features of each of the 100 images in the derivation cohort. These data were used to derive an EUS scoring system that was then validated by using the validation cohort by the expert endosonographer with the highest diagnostic accuracy. Results A total of 332 patients underwent EUS-FNA of a hepatic mass. Interobserver agreement regarding the initial endosonographic features among the expert endosonographers was fair to moderate, with a mean diagnostic accuracy of 73% (standard deviation 5.6). A scoring system incorporating 7 EUS features was developed to distinguish benign from malignant hepatic masses by using the derivation cohort with an area under the receiver operating curve (AUC) of 0.92; when applied to the validation cohort, performance was similar (AUC 0.86). The combined positive predictive value of both cohorts was 88%. Limitations Single center, retrospective, only one expert endosonographer deriving and validating the EUS criteria. Conclusion An EUS scoring system was developed that helps distinguish benign from malignant hepatic masses. Further study is required to determine the impact of these EUS criteria among endosonographers of all experience

Variation in Age at Cancer Diagnosis in Familial versus Nonfamilial Barrett's Esophagus

Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study we determine whether cancers develop at an earlier age in multiplex Familial Barrett’s Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC)